Preoperative hypofractionated radiotherapy in the treatment of localized soft tissue sarcomas

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Preoperative hypofractionated radiotherapy in the treatment of localized soft tissue sarcomas H. Kose1a-Paterczyk a,c, M. Szacht a,c, T. Morysi nski a, a,b a a I. qugowska , W. Dziewirski , S. Falkowski , M. Zdzienicki a, a  A. Pie nkowski a, K. Szamotulska b, T. Switaj , P. Rutkowski a,* a

Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Roentgena 5, 02-781 Warsaw, Poland b Department of Epidemiology, Institute of Mother and Child, Warsaw, Poland Accepted 29 May 2014 Available online - - -

Abstract Background: The primary treatment of soft tissue sarcomas (STS) is a radical resection of the tumor with adjuvant radiotherapy. Conventional fractionation of preoperative radiotherapy is 50 Gy in fraction of 2 Gy a day. The purpose of the conducted study was to assess the efficacy and safety of hypofractionated radiotherapy in preoperative setting in STS patients. Methods: 272 patients participated in this prospective study conducted from 2006 till 2011. Tumors were localized on the extremities or trunk wall. Median tumor size was 8.5 cm, 42% of the patients had tumor larger than10 cm, whereas 170 patients (64.6%) had high grade (G3) tumors. 167 patients (61.4%) had primary tumors. Patients were treated with preoperative radiotherapy for five consecutive days in 5 Gy per fraction, with an immediate surgery. Median follow up is 35 months. Results: 79 patients died at the time of the analysis, the 3-year overall survival was 72%. Local recurrences were observed in 19.1 % of the patients. Factors that had a significant adverse impact on local recurrence were tumor size of10 cm or more and G3 grade. 114 patients (42%) had any kind of treatment toxicity, vast majority with tumors located on lower limbs. 7% (21) of the patients required surgery for treatment of the complications. Conclusion: In this non-selected group of locally advanced STS use of hypofractionated preoperative radiotherapy was associated with similar local control (81%) when compared to previously published studies. The early toxicity is tolerable, with small rate of late complications. Presented results warrant further evaluation. Ó 2014 Elsevier Ltd. All rights reserved.

Keywords: Sarcoma; Soft tissue; Preoperative; Radiotherapy; Complications; Outcome

Introduction Soft tissue sarcomas (STS) are a rare, heterogeneous group of malignant tumors with mesenchymal origin.1,2 The principal treatment for patients with locally advanced STS is the surgical resection of the tumor with adequate margins combined usually with perioperative radiotherapy. Its addition showed to decrease the risk of local failure.3e5

* Corresponding author. Tel.: þ48 22 6439375; fax: þ48 22 6439791. E-mail address: [email protected] (P. Rutkowski). c Both authors equally contributed to the study.

The analysis of 6960 patients demonstrated survival benefit for the addition of radiotherapy to surgery in STS, especially for large, high-grade sarcomas.6 Radiotherapy in the treatment of STS can be used both before or after surgery,7 with comparable local control. STS are usually considered moderately radioresponsive tumors.8 Radiotherapy doses at range of 60e66 Gy are usually needed to be delivered postoperatively in order to eradicate microscopic disease.3 Hypofractionation is radiotherapy modality in which the total dose of radiation is divided into large doses per fraction with fewer fractions. Hypofractionated schemes of treatment are commonly used in palliative setting, for example for pain management of

http://dx.doi.org/10.1016/j.ejso.2014.05.016 0748-7983/Ó 2014 Elsevier Ltd. All rights reserved. Please cite this article in press as: Kose1a-Paterczyk H, et al., Preoperative hypofractionated radiotherapy in the treatment of localized soft tissue sarcomas, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.05.016

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bone metastases.9 However, it showed also comparable efficacy and safety to traditional fractionation in treatment of some solid tumors as breast,10e14 prostate15e17 or rectal cancer (where 5  5 Gy regimen is used).18,19 The conventional total dose and fractionation of preoperative radiotherapy in STS is 50 Gy in 25 fractions of 2 Gy. Radiobiological studies have shown that alpha/beta ratios of sarcoma cells may be below 10 Gy.20 Hypofractionation trials in tumor types with alpha/beta ratios below 10 Gy have shown equal local control compared to conventional fractionation.12,18 The above mentioned facts constituted the background for our study. The aim was to assess the efficacy and safety of hypofractionated radiotherapy in preoperative setting in patients with localized STS soft tissue sarcomas treated in one reference institution according to the uniform protocol. Patients and methods This prospective study included 272 patients treated in the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC) in Warsaw, Poland between January 2006 and June 2011. The study has been approved by the local Bio-Ethics Committee. All participating patients signed an informed consent. The study group comprised adult patients with locally advanced STS localized on the trunk wall or extremities, histologically grade 2 or 3 independent on tumor size or deeply seated (>10 cm) grade 1, both primary and after previous nonradical surgery outside our Center without further selection. All pathological diagnoses were confirmed in the Department of Pathology MCMCC, and all cases were assessed by multidisciplinary team (MDT). Treatment The radiotherapy schedule consisted of 5 Gy per fraction delivered in five consecutive days to total dose of 25 Gy. Before treatment the gross tumor volume (GTV), clinical target volume (CTV by adding 4 cm longitudinally and 2 cm transversely to primary tumor and reduced at surfaces of fascia and bones, unless invaded) and planning target (PTV adding 0.7e1-cm margin to CTV) volume were defined. The GTV involved the macroscopic tumor seen on the CT images. As the planning set was done without contrast the data from recent diagnostic CTs with contrast injection or MRI were also used to help contouring. The three dimensional conformal technique was used. The intensity modulated radiotherapy technique was allowed for lesions localized on the trunk. For tumors localized on the limbs immobilization devices were used. Six-MV photons were employed. The on-line portal imaging device was used every day to control the set-up of the treated volume. Wide local excision of the primary/recurrent tumor was performed, or re-excision of the scar with

wide margins if previous non-radical excision was done outside our Center, both in patients with superficial (n ¼ 10) and deeply (n ¼ 8) seated tumors after MDT decision if technically feasible. Surgery was performed within 3e7 days from the end of radiotherapy. The tissue flaps were used only in 10 patients (3.6%). The additional boost radiotherapy (30 Gy in 15 fractions on tumor bed þ 2 cm margins) was used in case of R1 surgical margins postoperatively in selected patients based on MDT decisions. The neoadjuvant chemotherapy was given before radiotherapy in selected patients at high risk of distant recurrence, with diagnosis of more chemosensitive subtypes (e.g. synovial sarcoma). Patient and tumor characteristics Patient characteristic is presented in Table 1. The median age was 55 years (range 17e86). The median maximal tumor dimension was 8.5 cm (range 1e41 cm). The median follow up was 35 months (range 6e94 months). Statistics Statistical calculations were performed with the software package SPSS v.15.0. The primary objective was to assess the local recurrence-free survival (LRFS), the secondary objectives were overall survival (OS) and treatment early and late complications. The LRFS and OS were estimated according to the KaplaneMeier method and the log-rank test was used for comparisons. LRFS time was calculated from the date of start of preoperative radiotherapy to the date of the most recent follow-up or local recurrence. OS time was calculated from the start of radiotherapy to the most recent follow-up, or death. In multivariate analysis of the factors associated with LFFS or OS, we used Cox proportional hazards models, that included all covariates significant in bivariate analysis. The differences were considered statistically significant if the p-values were<0.05. Results Local and distant recurrences Local recurrence (LR) after study treatment was diagnosed in 52 patients (19.1%), in 10 patients rescue amputation was performed thereafter. 3-year local LRFS rate was 81%, without further decrease in consecutive years in patients with longer follow-up; median LRFS was not reached. Factors correlated with poorer LRFS are shown in Table 2 tumor size larger than 10 cm, high grade tumors (G3), resection with microscopically positive margins (R1) and previous non-radical treatment. Patients with primary tumors treated in our Center had 3-year LRFS rate 80.5% compared to 74.6% in patients after previous unplanned surgery treated in our Center because of LR (Fig. 1). The

Please cite this article in press as: Kose1a-Paterczyk H, et al., Preoperative hypofractionated radiotherapy in the treatment of localized soft tissue sarcomas, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.05.016

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Table 1 Patient and tumor characteristics (n ¼ 272). Patient characteristics (n-272) Gender Female Male Age at the time of the diagnosis: 60 years >60 years Anatomic site of primary tumor Trunk Upper extremity Lower extremity Histological subtype Pleomorphic sarcoma Liposarcoma Other Synovial sarcoma MPNST Leiomyosarcoma Histological grade (*9 missing) 1 2 3 Tumor size (*6 missing) <5 cm 5e10 cm 10 cm Margin status R0 R1 Tumor status Primary tumor Recurrence after previous surgery Scar after previous surgery (Neo-)adjuvant chemotherapy Yes No Postoperative radiotherapy (boost) Yes No

Number of patients

%

3-year LRFS

p-Value

3-year OS

p-Value

145 127

53.3 46.7

85.3% 73.6%

0.048

75% 69%

0.390

164 108

60.3 39.7

82.5% 75.8%

0.388

76.8% 65.3%

0.012

37 44 191

13.6 16.2 70.2

77.8% 80.0% 80.2%

0.918

71.3% 81.6% 64.%

0.109

61 58 47 42 40 24

22.4 21.3 17.3 15.4 14.7 8.8

80.6% 80.9% 90.7% 83.1% 64.4% 73.4%

0.210

60.1% 78.9% 82.2% 88.9% 50.8% 61.4%

0.599

31 62 170

11.8 23.6 64.6

100% 85.4% 73.0%

<0.001

100% 82.9% 63.3%

<0.001

79 75 112

29.7 28.2 42.1

85.6% 81.6% 74.6%

0.058

89.2% 74.8% 61.1%

0.002

214 58

78.7 21.3

82.4% 70.7%

0.574

75.6% 60.5%

0.120

167 87 18

61.4 32.0 6.6

80.5% 74.6% 94.7%

0.850

68.6% 75.8% 94.4%

0.035

61 211

22.4 77.6

80.7% 79.7%

0.904

76.8% 72.3%

0.167

21 251

7.7 92.3

78.6% 80.0%

0.574

72.7% 72.3%

0.693

Abbreviations: MPNST e Malignant peripheral nerve sheath tumor. R0-complete removal of all tumor with microscopic examination of margins showing no tumor cells.R1-margins of the resected parts show tumor cells when assessed microscopically.

median follow up was 35 months. During follow-up in 96 patients (35.3%) the metastatic disease was diagnosed, the most commonly in the lungs.

for the LR group was 47% vs 78.9% ( p < 0.001) and for the metastatic patients 43.3% vs 91.1% ( p < 0.001). Treatment toxicity

Overall survival At the time of the analysis 79 patients had died, 65 due to a recurrence of sarcoma, 14 deaths were due to other causes, the 3-year OS rate was 72%, the estimated 5-year OS rate was 60%, median OS was not reached. Factors correlated with poorer OS are shown in Table 2. Use of perioperative chemotherapy did not have significant impact on OS, however, patients who received perioperative chemotherapy had usually worse initial prognostic parameters. Patients with LR and those diagnosed with metastatic disease had a strongly decreased chance of survival, when compared to those without relapses, the 3-year OS rate

In the treated group 114 (42%) of the patients had experienced any combined treatment-related adverse events (Table 3), 7% (21) of patients required additional surgery for the treatment of complications, usually a secondary closure of the wound. However, no amputations were required due to wound complications. Early toxicity (occurred within <6 months after surgery) The majority of the treatment complications were acute and reversible. Such complications concerned 32.4% (88)

Please cite this article in press as: Kose1a-Paterczyk H, et al., Preoperative hypofractionated radiotherapy in the treatment of localized soft tissue sarcomas, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.05.016

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Table 2 Factors having impact on local relapse free survival and overall survival. Local relapse free survival

Significance

Sex male (vs female) Margin status R1 (vs R0) Tumor size > 10 cm (vs <10 cm) Histological grade G3 (vs G2/G1) Surgery: scar/relapse (vs primary site excision) Overall survival Margin status R1 (vs R0) Age at the time of the diagnosis (>60 years) (vs <60 years) Tumor size > 10 cm (vs <10 cm) Histological grade G3 (vs G2/G1) Surgery: scar/relapse vs primary (vs primary site excision)

of all patients, most commonly in the lower limbs. Their distribution and factors correlated with early toxicity of the treatment are shown in Table 3. Late toxicities (>6 months after surgery) The late complications of the treatment were less common eoccurred in 14.7% (40) of the patients (12.4% in the group with preoperative radiotherapy only). The most common of such complications was the prolonged edema of the limb (9.2%). None of the patients had persistent edema higher than grade 2 when assessed using Stern’s Rating Scale for Edema.21 Increased tissue fibrosis was observed in 10 patients (3.7%) e 9 patients had grade 1 or 2 subcutaneous fibrosis, 1 patient had fibrosis grade 3 according to EORTC/RTOG Late Radiation Toxicity Criteria.22 The localization of the tumor had no impact on the occurrence of these complications. Pathological fractures of the bones which were involved in the treatment field occurred in 7 patients, all of whom had tumors localized on the lower extremities. The patient age, status of the tumor at treatment (primary vs previously treated) nor its size had no impact on the occurrence of the late complications. 1,0

Cum Survival

0,8

0,6

0,4

0,2

0,0 0

20

40

60

80

100

Figure 1. Impact of previous treatment on local relapse-free survival ( p ¼ 0.052).

Exp(B)

95% CI for Exp(B) Lower

Upper

0.020 0.026 0.031 0.001 0.052

1.957 1.425 2.061 4.012 1.936

1.112 0.772 1.070 1.802 0.993

3.444 2.630 3.968 8.930 3.773

0.053 0.019 0.013 <0.001 0.880

1.700 1.717 1.923 3.155 0.958

1.016 1.092 1.151 1.703 0.549

2.845 2.697 3.212 5.848 1.671

Discussion We present the largest series of unselected locally advanced STS patients treated with preoperative hypofractionated radiotherapy. Although in this prospective study the participants were predominantly patients with large, high-grade sarcomas, often after previous inadequate resection, it showed a comparable local control to previously published reports with conventionally fractionated preoperative radiotherapy, without significantly increased toxicity of the treatment.

The results of preoperative radiotherapy studies It has been proven that in the treatment of STS, adjuvant radiotherapy improves the local control rate when combined with conservative surgery with negative, marginal or minimal microscopic positive resection margins.23 Radiation therapy in the perioperative treatment of STS can be used both pre-and postoperatively, the effectiveness of both methods in local control of the disease, is comparable. In randomized trial performed by the National Cancer Institute of Canada (NCIC)24 182 patients received preoperative radiotherapy (50 Gy in 25 fractions) or postoperative radiotherapy (66 Gy in 33 fractions). The primary endpoint was the presence of a major wound complication. The study was prematurely closed because of significant difference in toxicity rate. It was not designed to assess primarily these end points, but it showed that the local recurrence rate, the regional or distant failure rate, and progressionfree survival did not differ between both groups. There were also published retrospective reports comparing the efficacy of those two radiotherapy modalities (using conventional dose fractionations). In the paper by Pollack et al. 128 patients received preoperative radiotherapy, and 165 patients postoperative radiotherapy the control rate at 5 years was 82% and 81%, respectively.25 In another paper coming from the MD Anderson Cancer Center patient treated with preoperative radiotherapy had 83% local

Please cite this article in press as: Kose1a-Paterczyk H, et al., Preoperative hypofractionated radiotherapy in the treatment of localized soft tissue sarcomas, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.05.016

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Table 3 Treatment toxicity. Factor (N )

Acute treatment toxicity

Anatomic site of primary tumor Trunk (37) Upper extremity (44) Lower extremity (191) Neoadjuvant chemotherapy Yes (61) No (211) Postoperative radiotherapy Yes (21) No (251)

Late treatment toxicity

All% (N ) 32.4% (88)

Inflammation requiring oral antibiotics% (N ) All 11.8% (32)

Wound dehiscence% (N ) All 11.8% (32)

Prolonged wound healing% (N ) All 16.5% (45)

All% (N ) 14.7% (40)

Prolonged edema% (N ) All 9.2% (25)

Increased tissue fibrosis% (N ) All 3.7% (10)

P [ <0.002

P [ 0.021

P [ 0.072

P [ 0.001

P [ 0.154

P [ 0.428

P [ 0.074

13.5% (5) 9.1% (4) 41.4% (79) P < 0.001

5.4% (2) 2.3% (1) 15.2% (29) P [ 0.084

5.4% (2) 4.5% (2) 14.7% (28) P [ 0.009

2.7% (1) 4.5% (2) 22% (42) P [ 0.021

5.4% (2) 20.5% (9) 15.2% (29) P [ 0.039

5.4% (2) 13.6% (6) 8.9% (17) P [ 0.088

0 9.1% (4) 3.1% (6) P [ 0.559

52.5% (32) 26.5% (56) P [ 0.005

18% (11) 10% (21) P [ 0.082

21.3% (13) 9.0% (19) P [ 0.082

26.2% (16) 13.7% (29) P [ 0.034

23% (14) 12.3% (26) P < 0.001

14.8% (9) 7.6% (16) P [ 0.016

4.9% (3) 3.3% (7) P < 0.001

4.8% (1) 34.7% (87)

0 12.7% (32)

0 12.7% (32)

0 17.9% (45)

42.9% (9) 12.4% (31)

23.8% (5) 8.0% (20)

23.8% (5) 2.0% (5)

control rate at 10 years, when compared with 72% with postoperative radiotherapy, with an unequal distribution of prognostic factors between the two groups with no differences in distant failure or overall survival. In Table 4 we presented the results of our series of patients in comparison to the existing data. In our group factors having a significant impact on LRFS were tumor grade and margins of resection. Such results are consistent with previously published papers.28 Local control was not significantly affected by the status of the tumor at the beginning of study treatment (primary vs recurrent). This differs from the experience of other centers,29 including our previous publication, where earlier improper treatment had a negative impact on the local control in liposarcoma patients.30 It may be related to biological selection bias of patients who were eligible for radical resection after unplanned surgery outside our institution.

Treatment complications In available studies it has been shown that preoperative radiotherapy increases the percentage of early treatment complications. However, these wound complications in majority of cases are reversible and have no significant long-term effects on function. Because of the bigger treatment field, and total doses used, the patients irradiated postoperatively tend to experience more serious late effects of the therapy7,24. Our data is in line with results of the randomized trial conducted by NCIC. The early complication rates were similar (32.4% vs 35%) in our and Canadian study, respectively. Of note, nearly 16% of patients treated preoperatively in NCIC trial required a second surgery for the treatment of complications. In our group it was only 7% of the patients. The use of preoperative chemotherapy

Table 4 Comparison of treatment results with major published studies. Study

Radiotherapy Patients Tumor sequence number grade

5  5 Gy

Preoperative radiotherapy Preoperative radiotherapy Postoperative radiotherapy Preoperative radiotherapy Postoperative radiotherapy Preoperative radiotherapy Postoperative radiotherapy Preoperative radiotherapy

O’Sullivan et al.24 2002

Pollack et al.25 1998

Zagars et al.26 2003

Hui et al.27 2006

272

Local control rate

128

65% 81% G3 83% Not analyzed G2 þ G3 83% G2 þ G3 67% 82%

165

73%

271

74% G3 70% G3 69% G3

94 96

246 67

81% p ¼ 0.07 83% 72% P ¼ 0.491 93%

Overall survival Wound complication rate

Estimated 5-years 60% 3-years follow up 85%

Not analyzed

Early toxicity Late toxicity

Surgery for treatment of the complications

32.4%

12.4%

7%

35%

Approximately 50%28 16%

17%

5.3%

25%

6%

Not analyzed

6% Estimated 5-years 63%

Estimated 5-years 73%

Not analyzed 5%

41%

9% P ¼ 0.03 7.4%

1.5% (eight patients from the whole study group)

18%

Please cite this article in press as: Kose1a-Paterczyk H, et al., Preoperative hypofractionated radiotherapy in the treatment of localized soft tissue sarcomas, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.05.016

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involved a significant risk of wound complications both acute and late. These correlations have not been showed in previously published reports.31 In terms of late toxicity the rates of late complications seem to be lower than presented by other authors. In the randomized trial grade 2 was 48.2% in the postoperative arm compared to 31.5% in the preoperative arm ( p ¼ 0.07). The edema was more frequent in the postoperative arm (23.2% vs. 15.5%) e in our group it was 9.2% and 3.7%, respectively.32 These results seem favorable for our study group, what is especially important that approximately 60% of STS patients will be ultimately cured. Better quality of life is an important issue. Especially dangerous toxicity for patients treated with radiotherapy and with tumor located in extremity is the bone fracture.33 In our group it occurred in case of 7 patients (2.5%).

treated with preoperative radiotherapy conventionally fractionated. Considering that the unselected group of patients participating in this study mostly consisted of high risk tumors, the results show good local control and toxicity which in vast majority is short-term and reversible, the rate of late complications was low. We believe that this method is worth of further studies and implementation in clinical practice.

Hypofractionated radiotherapy

1. Clark MA, Fisher C, Judson I, et al. Soft-tissue sarcomas in adults. N Engl J Med 2005;353(7):701–11. 2. The Maria Sklodowska e Curie memorial Cancer Center Department of Epidemiology and Cancer Prevention National Cancer Registry http://epid.coi.waw.pl/krn/english/ 3. Pisters PW, O’Sullivan B, Maki R. Evidence-based recommendations for local therapy for soft tissue sarcomas. J Clin Oncol 2007;25(8): 1003–8. 4. Pisters PW, Harrison LB, Leung DH, Woodruff JM, Casper ES, Brennan MF. Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. J Clin Oncol 1996; 14(3):859–68. 5. Yang JC, Chang AE, Baker AR, et al. Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 1998;16(1): 197–203. 6. Koshy M, Rich SE, Mohiuddin MM. Improved survival with radiation therapy in high-grade soft tissue sarcomas of the extremities: a SEER analysis. Int J Radiat Oncol Biol Phys 2010;77:203–9. 7. Haas RL, Delaney TF, O’Sullivan B, et al. Radiotherapy for management of extremity soft tissue sarcomas: why, when, and where? Int J Radiat Oncol Biol Phys 2012;84(3):572–80. 8. Soyfer V, Corn BW, Kollender Y, et al. Radiation therapy for palliation of sarcoma metastases: a unique and uniform hypofractionation experience. Sarcoma 2010;2010. Article ID 927972. 9. Tsuji S, Wara W. Palliation and benign conditions. In: Hansen E, Roach M, editors. Handbook of evidence-based radiation oncology. 2nd ed. Springer Science þ Business Media, LLC; 2010, p. 673–90. 10. Freedman GM. Hypofractionated radiation therapy in the treatment of early-stage breast cancer. Curr Oncol Rep 2012;14(1):12–9. 11. Whelan TJ, Pignol JP, Levine MN, et al. Long-term results of hypofractionated radiation therapy for breast cancer. N Engl J Med 2010; 362(6):513–20. 12. START Trialists’ Group, Bentzen SM, Agrawal RK, Aird EG, et al. The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet 2008;371(9618):1098–107. 13. START Trialists’ Group, Bentzen SM, Agrawal RK, Aird EG, et al. The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet Oncol 2008;9(4):331–41. 14. Owen JR, Ashton A, Bliss JM, et al. Effect of radiotherapy fraction size on tumour control in patients with early-stage breast cancer after local tumour excision: long-term results of a randomised trial. Lancet Oncol 2006;7:467–71. 15. Kupelian PA, Willoughby TR, Reddy CA, Klein EA, Mahadevan A. Hypofractionated intensity-modulated radiotherapy (70 Gy at 2.5 Gy

The efficacy and safety of the use of hypofractionated doses of adjuvant radiotherapy has been studied in several types of cancer.34,35 It was not associated with increased toxicity of the treatment and its effectiveness was not different from standardly used doses of radiotherapy. The rational for such approach is to enhance the therapeutic ratio by improving the local control or by decreasing the rate of complications, especially in tumors characterized by low alpha/beta ratio. The knowledge about alpha/beta rate has been verified in the last years. In many cancers this value is relatively lower than earlier supposed (<10). At present, there is only limited data for determination of alpha/beta ratio in sarcomas. Based on results for liposarcomas alpha/ beta ratio was estimated at 0.4 (1.4, 5.4).36 Sarcomas with such low alpha/beta ratio therefore should be extremely beneficial with hypofractionation. The most common regimen with preoperative hypofractionated radiotherapy in sarcomas was popularized by Eilber et al. The radiotherapy was delivered in 10 fractions of 3.5 Gy with immediate surgery. Before irradiation patients received intra-arterial doxorubicin. Local recurrence rate was 4% with 35% wound complication rate, 23% of patients required reoperation.37 Because of such high rate of serious toxicity schedule was modified. The total dose of radiation therapy was reduced to 17.5 Gy, but it resulted in a higher rate of local failure, so ultimately 28 Gy was delivered in 3.5 Gy daily fractions.38 In presented schedule we proposed irradiation to 25 Gy in five consecutive days. It results in a shorter overall treatment time what is important not only for departments with long waiting list for radiotherapy. This schedule is convenient for both, patients and physicians and also allows for lowering cost of treatment. Conclusions Our study demonstrated that local control rates and overall survival are similar to those seen in series of patients

Conflicts of interest The authors declare that there are no conflicts of interest.

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Please cite this article in press as: Kose1a-Paterczyk H, et al., Preoperative hypofractionated radiotherapy in the treatment of localized soft tissue sarcomas, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.05.016

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Please cite this article in press as: Kose1a-Paterczyk H, et al., Preoperative hypofractionated radiotherapy in the treatment of localized soft tissue sarcomas, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.05.016